AbstractBackgroundFormation and maintenance of appropriate neural networks require tight regulation of neural stem cell proliferation, differentiation, and neurogenesis. microRNAs (miRNAs) play an important role in brain development and plasticity, and dysregulated miRNA profiles have been linked to neurodevelopmental disorders including autism, schizophrenia, or intellectual disability. Yet, the functional role of miRNAs in neural development and postnatal brain functions remains unclear.MethodsUsing a combination of cell biology techniques as well as behavioral studies and brain imaging, we characterize mouse models with either constitutive inactivation or selectively hippocampal knockdown of the neurodevelopmental disease-associated gene Mir146a, the most commonly deregulated miRNA in developmental brain disorders (DBD).ResultsWe first show that during development, loss ofmiR-146aimpairs the differentiation of radial glial cells, neurogenesis process, and neurite extension. In the mouse adult brain, loss ofmiR-146acorrelates with an increased hippocampal asymmetry coupled with defects in spatial learning and memory performances. Moreover, selective hippocampal downregulation ofmiR-146ain adult mice causes severe hippocampal-dependent memory impairments indicating for the first time a role for this miRNA in postnatal brain functions.ConclusionOur results show thatmiR-146aexpression is critical for correct differentiation of neural stem cell during brain development and provide for the first time a strong argument for a postnatal role ofmiR-146ain regulating hippocampal-dependent memory. Furthermore, the demonstration that theMir146a^−/−mouse recapitulates several aspects reported in DBD patients, including impaired neurogenesis, abnormal brain anatomy, and working and spatial memories deficits, provides convincing evidence that the dysregulation ofmiR146acontributes to the pathogenesis of DBDs.